Neuromuscular blocking drugs are essential to the current discipline of surgery. More specifically, these drugs are used for routine procedures as endotracheal intubation, mechanical ventilation and muscular relaxation/paralysis. Naguib and Lien (Miller's Anesthesia), reporting on the history and clinical use of muscular relaxants (includes the drugs classified as neuromuscular blockers), wrote “the use of neuromuscular blockers in the operating room is quite common and has been important in the growth and development of anesthesia and surgery.” Such muscle relaxing agents not only “revolutionized the practice of anesthesia but also started the modern era of surgery and made possible the explosive development of cardiothoracic, neurologic and organ transplant surgery.”
Muscle relaxation is generally produced by depolarizing or non-depolarizing neuromuscular blockade. Depolarizing neuromuscular blockade, (e.g. using succinylcholine) causes failure of action potential generation, thereby leading to blockade. In contrast, non-depolarizing neuromuscular blockade, (e.g. using agents such as pancuronium, vecuronium, atracurium, mivacurium, rocuronium, pipecuronium, doxacurium, cisatracurium, rapacuronium) occurs due to a competitive inhibition of the acetylcholine receptor.
Despite the routine nature of surgical procedures, currently available neuromuscular blockers are insufficient in many aspects. In particular, it would be advantageous to have a drug that would specifically target a muscle type, e.g. diaphragm vs skeletal muscle, that would have rapid onset (e.g. seconds), a short duration of action (e.g. minutes), an effect that could be repeated without diminution or tolerance for the duration of interest, a rapid recovery (e.g. seconds or minutes), with no residual effect on muscle function (e.g. complete return to normal neuromuscular function), and eliminated unchanged as the parent molecule, thereby precluding any activity of metabolites.
Current agents are lacking in one or more of these respects. Succinylcholine, for example, has a rapid onset and extremely short duration of action but cannot be repeatedly used due to rapid tolerance to its effects. Likewise, the current non-depolarizing neuromuscular blockers have their own types of limitations, which include duration of effect (e.g. short acting—mivacurium; intermediate acting—vecuronium, rocuronium, atracurium, cisatracurium; long acting—pancuronium, pipecuronium, d-tubocurarine, metocurine, doxacurium). Thus, there exists a need for improvement in the art, in particular, a therapeutic that meets one or more of the advantages listed above that is not provided by currently available agents.
The instant disclosure addresses one or more of the aforementioned needs in the art.